This project aims to utilize high throughput screening to rescue the ASD-derived astrocytes cytokine signature. During this period, the collaborative team utilized the previously optimized high-throughput screening assay to screen a focused library, and a number of candidate compounds were identified that reduced toxic IL-6/8 levels. These candidates were advanced for testing in brain organoids and in vivo experiments using heterozygous Setd5 knockout mice, subjected to a battery of autism-related behavioral tests, to observe if they can rescue the disease phenotype. The mechanisms of action of these hits are currently being validated, and their activity profiles are being characterized in follow-up assays, such as glutamate uptake, neuron-astrocyte co-cultures and testing in brain organoids in dose response.